Amodestelevationinintracellular[Ca++](asaresultofincreasedcontractileactivity,forexample),hasbeenproposedtoactivateaCa++/calmodulin-dependentproteinphosphatase(calcineurin) thatcandephosphorylatethetranscriptionfactornuclear factor of activated T cells (NFAT), therebyfacilitatingtranslocationofNFATtothenucleusandultimatelypromotingproteinsynthesisandthushypertrophy(
Fig.13.7 ).ActivationofCa++/calmodulin-dependentproteinkinasehasalsobeenimplicatedinactivationofthetranscriptionfactormyocyte enhancer factor 2 (MEF2) bypromotingthedissociation(nuclearexport)ofaninhibitorofMEF2(namely,histone deacetylase [HDAC]).
Theimpairedβ-adrenergicresponseofcardiacmuscleafterchronicpressureoverloadinvolves,atleastinpart,adecreaseinβ-adrenergicreceptorsbecauseofinternalization.Bothphosphatidylinositol-3-kinase (PI3K) andβ-adrenergic receptor kinase 1 havebeenimplicatedintheinternalizationofβ-adrenergicreceptors.
Highbloodpressure,defectsinheartvalves,andventricularwallsweakenedasaresultofmyocardialinfarctioncanallleadtoheartfailure,aleadingcauseofdeath.Heartfailuremaybeseenwiththickeningofthewallsoftheventricleorwithdilation(i.e.,increasedvolume)oftheventricles.
Resultsofstudiessuggestthatdilatedcardiomyopathycanbepreventedinananimalmodelbydownregulatingphospholamban.ThemechanismunderlyingthispreventiveeffectofphospholambandownregulationisthoughttoinvolveanincreaseinCa++ uptakeactivityintheSRbecausephospholambantypicallyinhibitsSERCA.IncreasedactivityofSERCAwouldfacilitaterelaxationoftheheartasaresultofrapidCa++ uptakebytheSR.Inaddition,theforceofcontractionisincreasedbecausemoreCa++ isavailableforrelease.IncreasedCa++ uptakebytheSRmayalsodecreaseactivationoftheCa++-dependentphosphatasesthathavebeenimplicatedinthedevelopmentofcardiachypertrophy.
There is evidence that cardiac hypertrophy may not be associated with some functional impairments. Intermittent aortic constrictions, for example, result in decreased β-adrenergic signaling, decreased capillary density, and decreased SERCA2 levels, without evidence of hypertrophy. Activation of PI3K appears to be involved in this response.
278 SECTION3Berne & Levy Physiology Activity Ca++ Other transducers? Other effectors? Reprogramming Gene Expression Myocyte Hypertrophy/Tissue Remodeling CalcineurinCaMK Other targets? NFAT NFAT GSK3 HDAC CsA Cabin MCIP Agonists MEF2 GATA P •Fig. 13.7 Calcium-dependentactivationofcalcineurinandcalmodulin-dependentproteinkinasehavebeenimplicatedinthedevelopmentofcardiachypertrophyandinvolveactivationofthefollowingtranscriptionfactors:nuclearfactorofactivatedTcells(NFAT),transcriptionfactorbindingtoDNAsequenceGATA(GATA),andmyocyteenhancerfactor2(MEF2).Cabin,calcineurin-bindingprotein/inhibitor;CaMK,Ca++/calmodulin-dependentproteinkinase;CsA,cyclosporine;GSK3,glycogensynthasekinase3;HDAC,histonedeacetylase;MCIP,modulatorycalcineurin-interactingprotein.(RedrawnfromOlsonEN,WilliamsRS.Calcineurinsignalingandmuscleremodeling.Cell. 2000;101:689-692.) 1.